Abstract: Mechanoregulation of Tissue Morphogenesis Abstract Regenerative medicine holds great promise in treating degenerative diseases by stimulating damaged tissues to repair themselves, or replacing them with engineered tissues when the body cannot heal itself. A fundamental understanding of the regulatory mechanisms in tissue regeneration and the ability to modulate these processes, therefore, are critical to the ultimate success of regenerative medicine. Deviations of the regulatory processes as a result of genetic variation or environmental factors also represent the underlying causes of many diseases. However, little is known about how multi-progenitor systems interpret the cues in the microenvironment, such as global geometric guidance, local cell-cell interactions, and extracellular matrix properties, to collectively drive the morphogenic process of fashioning tissue structures across multiple length scales. Our recent studies suggest novel mechanoregulation schemes utilized by myogenic progenitors in the organization of striated muscle. The objective of this application is to develop an innovative cell mechanoregulation approach equipped with a set of novel technological modularities to elucidate the complex regulatory mechanisms during cellular self-organization. As a model system, the multi-stage myogenic self-organization process involving polarization, alignment, fusion, and myofibrillogenesis of muscle progenitors will be used to decipher the mechanoregulation of cellular self-organization during myogenesis. The project will address the long-standing biological question of multi-cellular self- organization, which drives the emergence of tissue morphogenesis. Successful completion of the project will establish the mechanoregulation approach for elucidating the regeneration processes of various tissues and will have profound impact on regenerative medicine in the future. Public Health Relevance: Regenerative medicine holds great promise in treating degenerative diseases by stimulating damaged tissues to repair themselves, or replacing them with engineered tissues when the body cannot heal itself. The proposed cell mechanoregulation study will allow us to understand the basic processes that govern the formation of tissue during normal development and diseases, and will eventually lead to novel approaches in regenerative medicine.